#400

Your daily dose of recent SGLT2 papers:

Study funded by the UK Medical Research Council (government body): Safety and effectiveness of SGLT2-inhibitors in people with type 2 diabetes over 70: UK population-based study using an Instrumental Variable approach. Not yet peer-reviewed, but it confirms the “very low” DKA risk, even among T2D (and especially among people less than 70yo). Unfortunately, no side-by-side SGLTi comparison in the paper:

Risk of DKA was increased with SGLT2-inhibitors in those aged ≥70 (Incidence risk ratio compared to DPP4i: 3.82 [95%CI 1.12,13.03]), but not in those <70 (1.12 [95%CI 0.41,3.04]). However incidence rates with SGLT2-inhibitors in those ≥70 was low (29.6 [95%CI 29.5,29.7]) per 10000 person-years. […] DKA is a rare AE and the risk increase with SGLT2-inhibitors may be restricted to adults over 70 […] Although we found DKA risk with SGLT2-inhibitors was elevated in those over 70, incidence was very low. […] SGLT2-inhibitors in older adults are effective and do not increase risk of dehydration, falls or urinary problems in older adults with T2D. However, risk of genital infections is increased, and DKA is a rare but severe adverse event of concern, meaning baseline DKA risk should be carefully assessed before initiation of SGLT2-inhibitors."

Meta-analysis of 17 RCTs (100k+ patients): GLP-1 receptor agonists, SGLT2 inhibitors and noncardiovascular mortality in type 2 diabetes: Insights from a meta-analysis 2024. (No side-by-side SGLTi comparison either. Similar results for GLP1RA btw, so they’re also quite good.)

Compared to placebo, SGLT2i significantly reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.82–0.99; I2 = 0 %; p < 0.05) along with cardiovascular mortality (RR = 0.84; 95%CI: 0.77–0.92; I2 = 28 %; p < 0.001).

Good review in the Journal of the American College of Cardiology: Hyperuricemia and Gout Reduction by SGLT2 Inhibitors in Diabetes and Heart Failure: JACC Review Topic of the Week 2024

SGLT2 inhibitors induce a state of starvation mimicry at a molecular, cellular, and physiological level, which is characterized by glycosuria and ketogenesis and by upregulation of nutrient deprivation signaling (ie, SIRT1) and downregulation of nutrient surplus signaling (ie, mTOR and HIF-1α). […] The actions of SGLT2 inhibitors to upregulate both SIRT1 and AMPK and downregulate both mTOR and HIF-1α are seminal to their cardioprotective and nephroprotective effects.

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Small study trying to understand why and how SGLT2i improve outcomes: Empagliflozin Improves Vascular Insulin Sensitivity and Muscle Perfusion in Persons with Type 2 Diabetes 2024

Following empagliflozin, insulin infusion improved endothelial function (p=0.02), lowered peripheral and aortic systolic (each p<0.01), diastolic (each p<0.05), mean arterial (each p<0.01), and pulse pressures (each p<0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each p=0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each p<0.05). We conclude that empagliflozin enhances insulin’s vascular actions which could contribute to the improved cardio-renal outcomes seen with SGLT2i therapy.

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#401

Can you comment on this - ages, genders, overall risk levels?

#402

In the paper they found: “SGLT2-inhibitors were associated with similarly increased risk of genital infection in both age groups (IRR <70 2.27 [2.03,2.53]; ≥70 2.16 [1.77,2.63]).”

So 2x the normal risk for genital infections, among people with T2D.

In people without diabetes, it’s less clear, see: Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials: "Low certainty evidence suggested that SGLT2 inhibitors increased the risk of urinary tract infection and genital infection […] Compared with placebo, SGLT2 inhibitors significantly increased the risk of urinary tract infection (RR: 1.29, 95% CI: 1.05 to 1.58, p=0.02; figure 3G; low certainty evidence, online supplemental table S2) and genital infection (RR: 2.44, 95% CI: 1.14 to 5.25, p=0.02; figure 3H; low certainty evidence, online supplemental table S2).

I think the risk is also lower for men.

tl;dr: the risk seems to be 2x placebo, whether T2D or not. So if you often have genital infections, you’ll have 2x more with SGLT2i. If you’ve never had genital infections then… :man_shrugging:

The risk seems higher with canagliflozin (Comparative Cardiovascular Benefits of Individual SGLT2 Inhibitors in Type 2 Diabetes and Heart Failure: A Systematic Review and Network Meta-Analysis of Randomized Controlled trials 2023) so maybe the risk ratio is less than 2 for dapagliflozin and empagliflozin.

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#403

Thanks!

Have never personally had an infection of these types, still I wonder is there a playbook of “preemptive steps”/protocol one could have to further mitigate the risk if taking an SGLT2i?

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#404

My doctor told me: “Just shake it well” :slight_smile:

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#405

If the following is true, then the 2X risks when on an SGLT2i may put the risk in the ball park of 20-25% also for men.

While women are more likely to suffer from urinary tract infections, about 12% of men will develop a UTI in their lifetime.

And I think UTIs can be worse in men than in women when they actually occur? Perhaps also inducing prostatitis due to infection, see the Peter Attia conversation with leading urologist Ted Schaeffer below if I remember correctly).

So it seems like minimizing the risks if one takes as SGLT2i makes sense

Here are some tings I found via a quick google search, if anyone else has ideas / things to consider would be great to get them listed out:

Urine helps clear bacteria out of the urethra, so peeing both before and after intercourse can help eliminate bacteria in your urinary tract. Other ways men can prevent urinary tract infections include:

  • Practice good hygiene: Regularly bathe genitals with soap and water to minimize growth and colonization of bacteria.
  • Avoid spermicidal lubricants: Lubricants can act as a vessel to transport and harbor bacteria. Avoiding lubricants can help prevent bacteria from entering the urethra.

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Drink plenty of fluids. If you have kidney, heart, or liver disease and have to limit fluids, talk with your doctor before you increase the amount of fluids you drink.

Urinate when you have the urge. Do not hold your urine for a long time. Urinate before you go to sleep.

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Older men have a higher risk of having a UTI, especially if they are after the age of 50. Most cases in older men stem from the bacterium known as Escherichia coli, which is naturally present in the body.

Cases similar to UTIs in younger men are typically caused by sexually transmitted infections (STIs).

A UTI develops when the bacterium gets into the urinary tract through the urethra and starts multiplying.

Risk factors include “a health condition or taking medication that suppresses the immune system”, so not sure how rapa played into things

Some of the sources:

Prostatitis due to infection: symptoms, pathogenesis, and treatment [46:45]; #273 ‒ Prostate health: common problems, cancer prevention, screening, treatment, and more | Ted Schaeffer, M.D., Ph.D. - Peter Attia

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Prostatitis, Antibiotics, and Rapamycin
#406

Checkout Dr. Francisco Gonzalez-Lima, a behavioral neuroscientist at The University of Texas at Austin talk about methylene blue. As I recall he says MB can be used to avoid UTIs

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#407

I edited my previous message because it seems that the 2x risk is for genital infections only, not UTIs.

This trial is also interesting: Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus 2020

The incidence of events consistent with urinary tract infections (UTI) was also similar for the empagliflozin 10/25 mg group versus placebo (9.27 vs. 9.70/100 patient-years, respectively). History of UTI was identified as a risk factor for UTI during treatment. Events consistent with genital infections occurred more frequently with empagliflozin 10/25 mg than placebo (3.54 vs. 0.95/100 patient-years, respectively). […] The frequency and incidence of events consistent with genital infections was higher among females compared with males […] As for UTIs, the majority of genital infections were non-serious, mild or moderate in intensity and led to treatment discontinuation in < 1% of patients […] The frequency of events consistent with genital infections was higher in patients with a history of chronic or recurrent genital infections compared with patients without such a history for both empagliflozin 10/25 mg and placebo (empagliflozin 10/25 mg: 22.7% vs. 5.4%; placebo: 7.9% vs. 1.5%, respectively) (Table ​(Table7).7). Moreover, complicated genital infection rates were consistently low and similar across groups (0.5% for both empagliflozin 10/25 mg and placebo)

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#408

That’s lifetime risk… which to me still seems like an amazingly low risk.

I’ve never had a UTI in my life or other genital infection. Seems like having a single or even a few bouts of UTI are a reasonable trade-off (for me at least).

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#409

Probably is how I’m coming out on the topic too. Still if there are things that can be done to cut the risk further that are low cost / low effort it may be smart to include those in a holistic protocol/playbook.

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#410

Another good paper: Prevention and Management of Genital Mycotic Infections in the Setting of Sodium-Glucose Cotransporter 2 Inhibitors 2020

The 3- to 4-fold increased incidence of GMIs is considered a classwide effect of SGLT2 inhibitors. Female sex and a prior history of GMIs are factors associated with the highest risk, whereas circumcised males are at the lowest risk of SGLT2 inhibitor-induced GMI. Personal hygiene advice can reduce the infection risk. When candidiasis occurs, it is often mild and responsive to treatment and often does not require discontinuation of the medication.

Here are the UK recommendations: https://www.imperial.nhs.uk/-/media/website/patient-information-leaflets/pharmacy/getting-the-most-from-your-sodium-glucose-cotransporter2-inhibitors.pdf?rev=c7c50dafb8bc4760aacc51a2d6c139fe&sc_lang=en

However, this is easily treated and a pharmacist or your GP can give you advice if irritation or itching occurs in these areas. Washing your genital area with warm water using non-perfumed soap and avoiding wearing tight underwear will reduce your risk.

Also from the first paper: Managing SGLT2 Inhibitor-Associated Genital Mycotic Infections

According to the review, optimizing diabetes management and providing personal hygiene education (ie, rinse genital area with water after voiding and before bed; wear cotton underwear) may help reduce the chance of genital mycotic infection in patients taking SGLT2 inhibitors.

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#411

The more I look at SGLT inhibitors the stronger the case seems to be for a longevity bet in humans

Anyone know why besides Peter Attia + the Nir Barzali/former NIA head ranking them at the top of their list of gerotherapeutics and Bill Faloon.Life Extension foundation, we not seeing a lot of momentum

  • eg not in there recent paper by Sinclair and others we’ve been discussing this week, not mentioned (much/at all?) by Matt K, not really discussed by any of the Healthpan / AgelessRX groups?
#412

That is an interesting question you bring up. Perhaps @szalzala can comment on Ageless RX’s take on SGLT2 inhibitors? Do they plan to offer them soon? What are the key issues they think that may be slowing adoption as a longevity therapeutic?

They are not yet offering it in their longevity product list: Longevity Prescriptions - Metformin, NAD+ Patches & More

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#413

I see 3 potential reasons:

  1. It’s a very recent class of drugs: first approved in the US in 2013/2014. (For instance, a friend told me that even for heart failure, for which they’re a massive proven game changer, not all French doctors prescribe them yet.)
  2. Evidence on their longevity properties is even more recent: the successful ITP results were published in late 2020.
  3. It’s not yet widely available as generics.
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#414

Good points!

I’ve been paying $60/month for Canagliflozin / Empagliflozin for the past few years… its easy to forget its still crazy expensive here in the US and in many markets. Most people interested in longevity are probably not wanting to spend $600/month on an SGLT2 inhibitor.

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#415

That’s 10x more than acarbose or metformin? No wonder people don’t take them.

A 4th reason may be the adverse events. They initially seemed quite bad (DKA, Fournier’s gangrene, UTI, etc.), but as time goes on, it looks like they’re rare and/or benign. For instance, in 2017, the FDA required a boxed warning on canagliflozin to warn of an increased risk of leg and foot amputations! In 2020, after investigating more, they removed the warning.

The case for SGLTi seems to get stronger every day, so unless we discover a terrible side effect, I assume people will slowly switch from metformin/acarbose to flozins. Brad Stanfield for instance wrote:

In terms of a so-called longevity medication, I think that SGLT2 inhibitors will be the first ones that will be prescribed and made widely available. That’s because they appear to provide significant protective effects for the kidneys. Our kidney function starts to decline from around the age of 30, so if we can use SGLT2 inhibitors to slow down or prevent that decline, that would be a powerful intervention. Of course, we’re waiting on the human data to come through, but there is a robust way of these things getting through to people.

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#416

The biggest barrier is cost. The pharmacy charges $600 for 30 tablets
We have an idea to bring down the cost. We’re going to be running a small trial to see if our idea works, and if it does then we could offer it at a more reasonable cost. But it’s still going to be expensive. There’s no way around that currently unless you get it from an overseas pharmacy (which you need to be careful of) or It goes generic

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#417

@adssx you have done an excellent job at describing the DKA and UTI pictures. Would you mind sharing more color and data on the gangrene/amputation risks/non-risk?

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#418

Very exciting. Any sense of the time line for that?

Is there a way to show interest in participating in the trial?

#419

Generic SGLT2 are already approved: Canagliflozin - Another Top Anti-aging Drug - #385 by adssx

We just need a few months for them to be available to customers I guess.

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